The present invention relates to a method for the topical treatment of acne vulgaris, seborrhea and hirsutism with steroid spironolactone and, in particular, to a method that provides therapeutically useful concentrations of the antiandrogen at its site of action, the sebaceous gland, whilst maintains the spillover of the drug into the blood stream at a very low level, thus preventing systemic side effects.
Seborrheic acne is a dermatological disease with high prevalence in teenagers of both sexes. It is characterized by the presence of inflammatory lesions usually localized in cheeks and forehead. These lesions are often accompanied by comedones. When bacterial growth is prominent the lesions become suppurative. In the most severe cases, the lesions are spread over the back and chest. In these forms of acne there are formations of cysts with purulent accumulations that connect each other subcutaneously.
Due to its potential for leaving scars together with the profound effect that this has on teenager personality it is important to treat acne and seborrheic condition.
High doses of oral spironolactone have been successfully used in the treatment of acne as well as hirsutism Shaw, J. C., J. Am. Acad. Dermat. 24:236-243, 1991.
The bibliographical information related to the treatment of these affections by means of antiandrogens reveals that until now, said treatments has been confined to:
i) the administration of spironolactone "per os" that reaches to the hypodermis, the dermis and the most deep layers of epidermis to compete with or inhibit the tissular testosterone; and PA1 ii) topical applications of formulations containing spironolactone. The previously mentioned limited permeation of the epidermis external layer explains the reduced penetration of the spironolactone and the poor effects of said topical applications. The systemic use of spironolactone, however can cause a variety of side effects, endocrine (since it is an aldosterone antagonist), neurologic and gastrointestinal, with an incidence that ranges from 75 to 91% Muhlemann, M. F. et al, British J. Dermatology 115:227-232, 1986; Hughes, B. R. et al., British J. Dermatology 118:687-691, 1988.
To circumvent these effects topical spironolactone has been tried Messina, M. et al., Current Therapeutic Research 34:319-324, 1983; Califano, L. et al., Clin Ther. 135:193-199, 1990; Pizzino, D. et al., Giornali Italiano Dermatologia Venerologia 122:599-604, 1987. However, this administration route proved not to be successful in view of the scarcity of publications and lack of commercial success. Also Walton Walton et al., British J. of Derm. 114:261-264, 1986, proved that commercially available preparations did not reduce sebum excretion. The hypothesis can be raised that these failures are related to the fact that the formulations used did not provide suitable permeation of the applied steroid to the site of action and that most of the spironolactone remained in the outer surface of the skin without crossing the barrier imposed by the stratum corneum. It should be noted that the skin separates the internal organs from the outside environment and serves as a protective barrier against the penetration of chemicals. It is an organ composed of many histological layers, and is described in terms of 3 major multilaminate layers: the epidermis, the dermis and the hypodermis. The epidermis is composed of five strata: stratum germinativum, stratum spinosum, stratum granulosum, stratum lucidum and stratum corneum. The later consists of many layers of compacted, flattened, dehydrated and keratinized cells that are rather physiologically inactive and are continuously shed and replenished from the innermost layers. This layer, due to the physicochemical properties of its cells is the main resistance to the entrance of external agents and acts as an efficient barrier. Molecules moving from the environment into the skin must first penetrate the stratum corneum and migrate following a concentration gradient. To increase skin permeability and in particular the permeability of the stratum corneum, and the amount of drug delivery by topical application, the skin may be treated either with the application of one or more permeation enhancer agent or else the drug and the permeation enhancer may be applied together.
Another approach for increasing the amount of drug delivered into the skin might be to include a higher concentration of the pharmaceutically active drug in the pharmaceutical preparation. The increase in the concentration of the drug would hopefully augment the amount permeated. This concept might work up to a certain extent but is limited by the amount of drug which can be permeated through the skin barrier, that acts as a rate limiting step.
Various compounds for enhancing the permeability of skin are known in the art.
Perhaps the most famous of such penetration enhancers is DMSO (dimethyl sulfoxide). However DMSO has not received FDA approval. Another well known substance is Azone.RTM. (R), see U.S. Pat. Nos. 3,909,816 1-dodecylhexahydro-2H-azepin-2-ona (Nelson Research Development); 4,311,481 and 4,316,893. U.S. Pat. No. 4,537,776 Cooper, 1985, has an excellent summary of prior art in the use of binary systems for permeability increase of the stratum corneum.
Recently Cooper, in "Increased skin permeability for lipophilic molecules", published in Journal of Pharmaceutical Sciences Vol. 73 No. 88 (1984), disclosed the use of oleic acid as a penetration enhancer in the presence of propylene glycol (see also U.S. Pat. No. 4,537,776).
Neodecanoic acid has been shown to be a potent enhancer of naloxone permeation with a low irritation profile Aungst, B. J., Pharm. Res. 6:244-247, 1989. Also pyrrolidone derivatives have been shown to increase the permeability of the skin to several compounds by Sasaki, 1990, Sasaki, H. et al., Int'l. J. of Pharmaceuticals 60:177-183, 1990 and also lauramide derivatives by Mirejovsky and Takruri, 1986 Mirejovsky, D. et al., J. of Pharm. Sci. 75:1089-1093, 1986.
However, none of the above mentioned inventions or publications deals with the study of spironolactone.
Moreover as pointed by Chien in "Transdermal Controlled Systemic Medications", Marcel Dekker INC, New York 1987, pages 69-75, an enhancer increases the permeation of different compounds to different degree. There are not such general or universal enhancers. As an example we can quote results of this author as wherein below indicated:
______________________________________ ENHANCEMENT FACTOR BY PROPYL COMPOUND AZONE PROPYLOLEATE MYRISTATE ______________________________________ Progesterone 6.0 5.4 4.6 Estradiol 20.2 14.6 9.3 Hydrocortisone 61.3 5.0 4.6 Indomethacin 14.5 4.7 3.8 ______________________________________
This type of result clearly indicates that optimal permeation of a given compound can be achieved only by careful experimentation as shown in our Argentinean Patents Applications N. 315.433 and 314.479.